A nomogram by adding atrial fibrillation to multicenter stroke survey score to predict intracranial hemorrhage in stroke patients undergoing thrombolysis

Background: Identiﬁcation of stroke patients at risk of postthrombolysis intracranial hemorrhage (ICH) in the clinical setting is essential. However, studies in this area spare.We aimed to develop a nomogram by adding atrial fibrillation to the Multicenter Stroke Survey (MSS) score to predict the probability of ICH in acute ischemic stroke patients undergoing thrombolysis. Methods: A retrospective observational study was conducted with 287 participants from a single center (67.2% males, median age 65 years). Head computed tomography scan was performed after 24 hour to evaluate ICH occurrence, and a computed tomography scan was done immediately in case of clinical worsening. The risk factors associated with ICH were analysed. Based on multivariate logistic model, a nomogram was generated for ICH on the basis of atrial fibrillation and the MSS score. We assessed the discriminative performance by using the area under curve (AUC) of receiver-operating characteristic (ROC) and calibration of risk prediction model by using calibration plot. Results: A total of 41(14.3%) ICH events occurred.The MSS score and atrial fibrillation were independent predictors of ICH in multivariate logistic regression analysis. Discrimination of the nomogram was superior to the MSS score alone (0.794 vs 0.741; P=0.034). The model was internally validated by using bootstrap (1000 samples) with AUC-ROC of 0.795. The calibration plot showed good agreement. Conclusion: We developed and internally validated a new nomogram using the MSS score and atrial fibrillation as predictors.The nomogram is a simple and accurate tool for predicting ICH in acute ischemic stroke patients undergoing thrombolysis. Further studies are warranted to validate our findings.

A nomogram by adding atrial fibrillation to multicenter stroke survey score to predict intracranial hemorrhage in stroke patients undergoing thrombolysis Stroke is a leading cause of death and disability worldwide. Intravenous recombinant tissue plasminogen activator (r-tPA) treatment is an effective therapy for acute ischemic stroke [1]. However, intracerebral hemorrhage (ICH), especially symptomatic ICH (sICH), is the main complication of thrombolytic therapy and may increase the risk of poor and fatal outcomes [2]. The ICH occurrence rate after thrombolysis varies by ethnicity, and the rate of ICH is reported to be 2.12-fold higher in Asian populations than in non-Asian populations [3,4].
Accurate identification of stroke patients at increased risk of future postthrombolysis ICH in the clinical setting is essential. Several prognostic scores have been applied to identify stroke patients with a high risk of postthrombolysis ICH [5,6]. The Multicenter Stroke Survey (MSS) score has been shown to be a useful tool to predict sICH in Chinese population [5]. The MSS score is based on four variables (age, platelet count, glucose level and National Institute of Health Stroke Scale (NIHSS) score on admission) that are available before thrombolysis treatment [7]. In addition, the MSS score does not require imaging, making it particularly suitable for nonneurologists. However, the predictive value of the MSS score varied and was poor in some studies [5,6,8], which might be due to some potential risk factors not fully captured by the scoring system when used in different populations. Growing evidence supports that atrial fibrillation (AF) is an independent risk factor for ICH events and is associated with poor outcomes in acute ischemic stroke patients undergoing thrombolysis [9,10]. However, few score systems for ICH after thrombolysis had considered AF as a predictor.
Nomogram is a useful and better visual tool to predict clinical outcomes than the conventional scoring systems. It is a graphical statistical instrument that incorporates some variables to develop a scoring system, which reflects the individual and precise risk probability. However, the prognostic nomogram for ICH events in stroke patients 4 undergoing thrombolysis is currently lacking [11,12].
The aim of the present study was to develop a nomogram by adding AF to the MSS score to predict the probability of ICH in acute ischemic stroke patients undergoing thrombolysis.  (Fig 1). Patient data were extracted from their medical charts. This retrospective study was reviewed and approved by the Institutional Review Board of Xi'an Jiaotong

Study Population and Design
University. The need for patient consent was waived by the same ethics committee.

Baseline Data Collection
The baseline demographic, clinical and laboratory information collected included age, sex; current smoking status, glucose level on admission, triglyceride (TG) level, low-density lipoprotein cholesterol level (LDL-C), platelet count; antiplatelet therapy before enrollment, systolic and diastolic blood pressures, NIHSS score on admission, symptom onset to treatment (ONT), and histories of hypertension, diabetes mellitus and AF.

Calculation of the MSS Score
The MSS score has been previously described [7]. The score was derived from four variables (age > 60 year, platelet count ≥ 150,000/mm 3 , glucose level >8.325 mmol/L and NIHSS score > 10 on admission) and calculated for each patient. All baseline MSS scores at discharge were calculated by a stroke neurologist.

Thrombolysis Method
All patients were treated with r-tPA within 4.5 hours of onset. Intravenous r-tPA (alteplase, 0.9 mg/kg up to a maximum of 90 mg) was used with 10% of the total dose as a bolus, followed by a 60-min infusion of the remaining dose.

Ascertainment of Intracranial Hemorrhage
On admission, all patients underwent a CT scan within the first 4.5 hours of stroke onset.
CT was repeated 24 hours after intravenous r-tPA, and another CT scan was performed immediately in cases of rapid neurological deterioration to evaluate the presence of ICH.
SICH was defined as any type of ICH on any posttreatment imaging after the initiation of thrombolysis and an increase in NIHSS by 4 points from baseline or death; asymptomatic ICH (aSICH) was defined as any type of ICH on any posttreatment imaging after thrombolysis start but not accompanied by neurological deterioration (the European Cooperative Acute Stroke Study II, ECASS II) [13].

Statistical Analysis
Descriptive analysis was conducted with continuous variables described as medians with interquartile ranges ( The MSS score could range from 0 to 4 with an increasing score corresponding to an increase in postthrombolysis ICH incidence (online supplement Fig 1). The ICH incidence for the MSS score of 0, 1, 2, 3 and 4 was 3.9%, 4.8%, 22.1%, 30% and 50%, respectively.

Risk score and nomogram development
A` nomogram based on AF and the MSS score was developed from the results of multivariate logistic regression by assigning a weighted score to each of the two independent prognostic factors. The discriminative performance of the nomogram (evaluated by means of AUC-ROC) was 0.794 (95% CI 0.745-0.840) in the present study.
The AUC increased from 0.741 for the MSS score alone to 0.794 for the MSS score combined with AF (difference in the AUCs, 0.053, z value 2.12, P=0.034) (Fig 2). The

Discussion
The present study demonstrated that adding AF to the MSS score increased the predictive value of the MSS score for ICH. We developed and internally validated a nomogram based on AF and the MSS score to predict the probability of ICH in stroke patients treated with alteplase. The new nomogram showed a significantly higher predictive accuracy than the conventional scoring system of the MSS score.
Among the computational models for predicting prognosis, the nomogram is very useful because it is a pictorial representation of a statistical predictive model that generates a 8 numerical probability of a clinical event. It is more accurate than the conventional method using OR [14]. Therefore, we constructed a nomogram that can calculate the probability of ICH for an individual stroke patients undergoing thrombolysis. The parameters constructed in our model are easily available in almost all medical centers and all patients within few minutes of their arrival to the emergency room.
To the best of our knowledge, there have only 2 works carried out on nomograms for individualized prediction of the ICH probability in acute ischemic stroke patients undergoing thrombolysis [11,12]. The STARTING-SICH nomogram including 10 variables was designed to predict sICH in stroke patients treated with intravenous thrombolysis in a large cohort study of Italy [11], but it has not been external validated in Asian patients and the data on ethnicity are lacking. The other nomogram model including 3 variables (present of AF, NIHSS score and glucose level on admission) was developed in Asian patients [12]. However, the study did not include the information about the total dose of r-PA, and the risk of ICH is reported higher in Asian populations at standard doses [15].
Our nomogram used only two prognostic factors including AF and an existing scoring system (the MSS score). The MSS score is widely used. History of AF is easily and readily obtainable during the patient's admission at the hospital. Our nomogram was the first approach to combine AF and the MSS score to predict ICH in stroke patients. This combination approach had more accurate predictive power than the MSS score alone.
Researchers recently compared different ICH risk scores and found that ORs based on logistic models and AUC-ROC values for the MSS scores showed improved performance, with values ranging from 0.63 to 0.86 [5,6,8]. The present study demonstrated that the AUC-ROC value for the MSS score was 0.741 for ICH, and the predictive value increased significantly to 0.794 when the MSS score was combined with AF. This easy-to-use simultaneous testing model that adding AF to the MSS score, with noninvasive clinical characteristics, can provide an immediate and reliable estimation of ICH risk in acute ischemic stroke patients who require thrombolysis. This estimate will guide clinicians not only in counseling patients and/or families but also in the early identification of those patients at high risk of ICH as well as support decisions regarding additional treatments or more attention.
Early ischemic signs on CT or even hyperdense cerebral artery signs are difficult to interpret and require experienced personnel or experts to evaluate, as reported by Thanin et al [16]. Therefore, some scoring systems, including the MSS score [7], Safe Implementation of Thrombolysis in Stroke (SITS)-SICH score [17], Glucose Race Age Sex Pressure Stroke Severity (GRASPS) score [4] and Stroke Prognostication using Age and National Institutes of Health (NIH) Stroke Scale (SPAN-100) positive index [18], have no CT component in their scoring systems. Most scoring systems are derived from Western countries that might have different sets of prognostic parameters. The MSS score was derived from a North American and European study within a 3-hour time window, whereas the present study with a Chinese study employed a 4.5-hour time window. A previous study reported that the MSS score could predict sICH (ECASSII definition) with an AUC of 0.730 in Chinese stroke patients [5]. The AUC for the MSS score alone was 0.741 for ICH in the present study; therefore, we speculated that this result might be due to some potential risk factors not fully captured by the scoring system when external validated in Chinese population.
Studies have reported additional predictive factors for postthrombolysis ICH, including leukoaraiosis, high mean blood pressure, low serum albumin and the neutrophil to lymphocyte ratio [19][20][21][22]. However, these identified risk factors accounted for only a proportion of the stroke patients who presented ICH after intravenous thrombolysis.
Growing evidence supports that AF is an independent risk factor for ICH events [9,10,23].
However, AF has not been considered in previous risk scoring systems for ICH after thrombolysis [4,7,17,18,24,25]. Yeo et al reported a scoring system using nomogram based on three variables (presence of AF, glucose level and NIHSS score) was a practical tool to predict the risk of ICH after thrombolysis [12]. In our study, the AF prevalence at baseline was higher in patients with ICH and was an independent risk factor for ICH in stroke patients undergoing thrombolysis. Furthermore, we found that AF and the MSS score were correlated, and the patients with AF had higher MSS score. Moreover, adding AF to the MSS score on admission enhanced the predictive value of ICH for stroke patients with thrombolysis.
We included both symptomatic and asymptomatic postthrombolysis ICH as the outcome for the scoring systems, as in previous studies [7,12]. Many reports have demonstrated that both symptomatic and asymptomatic ICH may worsen clinical outcomes [7,26,27], and influence the timing of reintroducing antithrombotic treatment after r-tPA treatment.
Furthermore, predicting a higher risk of ICH preceding intravenous thrombolysis may help clinical decision making by slanting treatment toward only mechanical thrombectomy without intravenous r-tPA [12].
There are some limitations of the study. First, the present study used a retrospective design, so some confounders were not available for inclusion in our multivariate analyses.

Availability of data and materials
Data used for this study cannot be made publicly available because additional studies are currently under way using the same data set, but are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
This retrospective study was reviewed and approved by the Institutional Review Board of Xi'an Jiaotong University. The need for patient consent was waived by the same ethics committee.

Consent for publication
Not applicable. Abbreviations: OR, odds ratio; CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale; MSS, multicenter stroke survey.
*Adjusted for: symptom onset to treatment and antiplatelet therapy.